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The pathogenesis of Niemann–Pick type C disease: a role for autophagy?

  • Chris D. Pacheco (a1) and Andrew P. Lieberman (a1) (a2)


Niemann–Pick type C disease (NPC) is a sphingolipid-storage disorder that results from inherited deficiencies of intracellular lipid-trafficking proteins, and is characterised by an accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. Patients with this disorder develop progressive neurological impairment that often begins in childhood, is ultimately fatal and is currently untreatable. How impaired lipid trafficking leads to neurodegeneration is largely unknown. Here we review NPC clinical features and biochemical defects, and discuss model systems used to study this disorder. Recent studies have established that NPC is associated with an induction of autophagy, a regulated and evolutionarily conserved process by which cytoplasmic proteins are sequestered within autophagosomes and targeted for degradation. This pathway enables recycling of limited or damaged macromolecules to promote cell survival. However, in other instances, robust activation of autophagy leads to cell stress and programmed cell death. We summarise evidence showing that autophagy induction and flux are increased in NPC by signalling through a complex of the class III phosphoinositide 3-kinase and beclin-1. We propose that an imbalance between induction and flux through the autophagic pathway contributes to cell stress and neuronal loss in NPC and related sphingolipid-storage disorders, and discuss potential therapeutic strategies for modulating activity of this pathway.


Corresponding author

*Corresponding author: Andrew P. Lieberman, Department of Pathology, University of Michigan Medical School, 3500 MSRB 1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA. Tel: +1 734 647 4623; Fax: +1 734 615 3441; E-mail:


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There are several excellent recent reviews on autophagy and disease, including:

Levine, B. and Kroemer, G. (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42
Mizushima, N. et al. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075

The Ara Parseghian Medical Research Foundation supports scientific research on Niemann–Pick type C disease and related disorders. Their website includes information about the Foundation, the diseases they target with research support, and links to other sources of information:


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